British Patent Specification No. 1,200,886 discloses certain arylethanolamines, which are theraputically active compounds useful as antihypertensive and bronchodilating agents, and two methods for their preparation.
British Patent Specification 1,200,886, "Pharmazeutische Wirkstoffe (Synthesen, Patente, Anwendungen)", Vol. 5, by Kleeman and Engel (2nd Edition, New York and Stuttgart), p. 813, 1982 and "Pharmaceutical Manufacturing Encyclopedia", Second Edition, Vol. 1, by Marshall Sittig, Noyes Publications, Park Ridge, N.J., U.S.A., 1988, pp. 31-33, teach the preparation of albuterol by condensation of a haloacetophenone with a benzyl protected t-butyl amine. These processes have the disadvantage of producing albuterol in low yields with a significant generation of waste or undesirable by-products. Part of this inefficiency is due to the requisite use of multiple reducing agents, i.e. lithium aluminum hydride, sodium borohydride and hydrogenation with palladium/carbon catalysts, accompanied by multiple clean-up procedures. Another reason for the inefficiency is the requisite use of a benzyl-protecting group on the amine to prevent dialkylation of the amine, necessitating further deprotection and clean-up procedures.
British Patent Specification 1,247,370 teaches the preparation of albuterol by condensation of t-butylamine with arylglyoxal, followed by multiple reductions using lithium aluminum hydride and sodium borohydride. This patent also teaches a process for preparing arylglyoxals requiring multiple steps using low temperatures (e.g. room temperature) and long reaction periods (e.g. up to one week) to minimize undesirable polymerization of the labile arylglyoxal. This process has the disadvantage of producing albuterol in low yields with significant generation of undesirable by-products.
Arylglyoxals are compounds useful as intermediates for preparing pharmaceutical compounds. Conventional processes for preparing arylglyoxal compounds are known in the art. N. Kornblum, J. W. Powers, G. J. Anderson, W. J. Jones, H. O. Larson, O. Levand and W. M. Weaver, JACS, Vol. 79, (1957) page 6562, J. March, Advanced Organic Chemistry, Reactions, Mechanisms, and Structure, Third Edition, John Wiley & Sons, New York, N.Y., (1985) pp. 1081-1083 and British Patent Specification 1247370 teach the oxidation of primary halides and esters of primary alcohols to aldehydes with dimethyl sulfoxide. M. B. Floyd, M. T. Du, P. F. Fabio, L. A. Jacob and Bernard D. Johnson, J. Org. Chem. Vol. 50, (1985), pp. 5022-5027 and R. Desmond, S. Mills, R. P. Volante and I. Shinkai, Synthetic Comm. Vol. 19 (3 and 4), (1989) pp. 379-385 disclose the reaction of acetophenones with aqueous hydrobromic acid (HBr) in DMSO leading to the formation of arylglyoxals. G. Cardillo, M. Orena and S. Sandri, J.C.S. Chem. Comm. (1976) pp. 190 disclose the preparation of aldehydes by reacting alkyl halides with potassium chromate in hexamethylphosphoramide in the presence of crown ethers. K. R. Henery-Logan and T. L. Fridinger, Chemical Communications, (1968) pp. 130-131 disclose the conversion of .alpha.,.alpha.-dichloroacetophenone with sodium methoxide in methyl alcohol to phenylglyoxals. V. E. Gunn and J. P. Anselme, J. Org. Chem., Vol. 42, No. 4, (1977) pp. 754-755 disclose the conversion of phenacylbromides to phenylglyoxals with N,N-diethyl and N,N-dibenzylhydroxylamines. H. A. Riley and A. R. Gray, Organic Synth. Coll. Vol. 2, pp. 509-511 disclose the conversion of acetophenone to phenylglyoxal with selenium dioxide as the oxidant. The above-cited processes have severe limitations. For example, most of these references teach the direct preparation of arylglyoxals, which may be labile or unstable. Also, such processes generally are not adaptable to using a wide range of substrates or precursors to prepare arylglyoxals. In addition, most of the cited processes utilize toxic oxidants such as selenium oxides, chromates and the like which tend to be unsuitable for preparing pharmaceutical compounds.
Moreover, we have found that the use of aqueous hydrogen bromide as a brominating agent was not adaptable for certain aryl substrates since use of the aqueous reagent resulted in undesirable ring bromination.
In view of the problems with processes taught in the prior art, it would clearly be desirable to provide a new process for preparing arylethanolamines such as albuterol in higher yields and with reduced waste or generation of by-products. It would also be desirable to provide new intermediates or derivatives for preparing albuterol which would result in a simplified preparation of this compound. We have surprisingly found that the foregoing objectives may be achieved by utilizing specified precursors for preparing the arylglyoxal hydrates, that is, the acetals and hemi-acetals. These acetals and hemi-acetals, which we have found to be significantly more stable than the arylglyoxal hydrates, may be deprotected under relatively mild conditions to yield the desired hydrates of the arylglyoxal. Furthermore, we have found a single reducing agent which may be used for preparing albuterol, instead of the multiple reducing agents of British 1,247,370 and 1,200,886. It would also be desirable to provide a process which requires fewer reaction and cleanup steps than other processes previously taught. In addition, it would also be desirable to provide an efficient process for preparing the acetal and hemi-acetal derivatives which can serve as substrates or precursors for preparing the desired hydrates of arylglyoxals. By employing such intermediates and processes, it is believed that many of the limitations and problems of the processes described in the above references for making albuterol can be overcome.